Relevance. "Category A" hemorrhagic fever viruses (HFVs), such as Rift Valley fever virus (RVFV), have been under active development for use as BWT agents. Despite extensive effort, no effective medical countermeasures are currently available to combat these threats. Thus, the ability to rapidly generate anti-HFV therapeutics is essential to protect U.S. civilians and Forces, thereby preventing potentially devastating casualties associated with HFV infections. Background. Since current approaches to developing antiviral compounds are extremely costly and time-consuming, but rarely successful, we have developed a revolutionary technology to rapidly generate therapeutics to cytolytic pathogens. Objectives. Our pathogen-selected anti-pathogen technology utilizes diverse (i.e., 10e8) cell-resident combinatorial protein libraries (termed adaptein libraries). We propose to screen these libraries to identify novel broad-spectrum therapeutics that protect cells from challenge with "Category A" HFVs. These therapeutics are designed for use before or after exposure to BWT agents to prevent civilian and military casualties. Study design. To successfully accomplish this innovative project, we have assembled a multi-disciplinary team of expert virologists, microbiologists and structural biologists. Complex adaptein libraries have been integrated into mammalian cells, such that each cell expresses a unique member of the adaptein library. We will challenge these heterogeneous cell populations with RVFV. Cells that survive virus challenge will be selected, cloned, and the protective adaptein responsible for antiviral activity identified by nested-PCR sequencing. Purified cell-permeant variants of each protective adaptein will be developed as therapeutic agents, and the efficacy of these adapteins to protect cells and animals from RVFV will be determined from dose-response studies. During project year 2, our new BSL-4 facility will be available to apply our strategy to other HFVs, and thus test the efficacy of our adapteins against these viruses. In this manner, compounds that provide broad protection against different HFVs will be generated. A significant strength of our technology is that it eliminates the a priori assumptions inherent within target-based or computational drug discovery methods, ultimately allowing our technology to discover novel therapeutics to BWT or emergent pathogens without the need for detailed pathogen characterization.